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Award Ceremony Speech

Presentation Speech by Professor G.
Liljestrand, member of the Staff of Professors of the Royal Caroline Institute,
on December 10, 1936

Your Majesty, Your Royal Highnesses, Ladies
and Gentlemen.

In the second book of his famous work on the history of Rome,
Livy has described how Menenius Agrippa, sent out by the Senate
to attempt to bring about a reconciliation with the Plebeians who
were on strike, told them the fable of the revolt of the limbs
against the stomach, stressing the necessity of the cooperation
of all parts in the interest of the whole. This cooperation, or
«consensus partium», described here in a simple form,
is the main objective of physiological research. To a large
extent it is brought about by the body fluids and especially by
the blood. These not only effect the necessary distribution of
the supply from outside, but also the removal of waste products;
the intensive research done today on internal secretions has also
shown how important it is that the various hormones should be
distributed by this means, from the organs in which they are
produced to other parts of the body. Characteristic of the whole
pattern of this cooperation, either humoral or chemical, is the
fact that it is established relatively slowly but extends over a
considerable time. Simultaneously also, another mechanism is set
up, through the development of the nervous system, which permits
the exchange of rapid messages and their swift transposal into
action. Occasionally such messages are sent out through an act of
will which brings the skeletal muscles into action. But our inner
organs also are under the influence of the nervous system. The
heart beats which are accelerated by work and mental emotion, the
pupils which contract when light enters the eye, and the
gastro-intestinal canal which, through its movements, dispatches
food according to its kind are examples of how activity adapts
itself to the influence of certain nerves which, in these
instances, are not under the command of the will. In this portion
of the nervous system, then, there is a kind of self-government
and it is therefore known as the autonomic nervous system. This
is composed of two main parts, which are both of equal
importance, but which to a certain extent represent conflicting
interests. Taking the heart as an example, one section, the
so-called sympathetic system, conveys those impulses which
accelerate beating, while the parasympathetic system on the other
hand conveys those which have a slowing-down effect.

If external work has to be performed, or if dangers threaten,
then the sympathetic part of the autonomic nervous system takes
over the direction and develops increased activity. The heart
pumps more blood, the muscles are put into a state of defence and
receive an extra supply of fuel, while, at the same time, there
is a momentary cessation of activity in a variety of other
places, for instance in the movements of the intestinal canal. In
contrast, different activity occurs in the parasympathetic system
as local conditions require, for instance in the function of a
single organ.

It was generally thought that impulses in the nerves act directly
on the muscles or glands bringing about a change in their
activity. But as early as 1904, Elliott presented a different
interpretation. From the medulla of the adrenal glands, which, as
embryonic development shows, is related with the sympathetic
nervous system, a substance can be produced, i.e. adrenaline, the
effect of which is remarkably similar to that produced by
increased activity in the sympathetic system. Elliott therefore
supposed that the impulses in the sympathetic nerves produced a
release of adrenaline in the nerve endings which would then be
the real vehicles of the stimulation effect. Ten years later,
Dale published a comprehensive investigation of another
substance, acetylcholine, for which he found a corresponding
conformity with the effect of the parasympathetic stimulation.
As, however, at that time acetylcholine had not been met with in
the body, there was not sufficient basis for a discussion as to
whether it normally transmitted impulses.

While the idea that nerve stimulation could be brought about by
the release of certain substances was not entirely new, it is
nevertheless thanks to Loewi that the idea was brought from the
realm of unproven hypotheses on to the firm ground of certain
experience. He first used a heart with its nerve trunk, removed
from a frog or toad, connecting up the heart chamber with a small
glass container in which was a small quantity of a suitable
nutrient fluid. If the nerve trunk was stimulated by electrical
means, the number and strength of heart beats altered according
to circumstances there are, namely, in the nerve trunk fibres
from both the sympathetic and the parasympathetic systems. If
after such stimulation Loewi transferred the fluid which had been
pumped in and out of the heart into another similarly prepared
heart, he found that the fluid itself had taken on properties
capable of producing changes in the activity of the organ
corresponding to those which had earlier been produced by the
nerve stimulation. Through this very simple but ingenious
experiment it was proved that the nerve stimulus can release
substances having the action characteristic for the nerve
stimulation and further observations left no doubt whatever that
the nerve stimulus itself was passed on to the organ by chemical
means.

Painstaking work now began with the object of determining the
nature of the substances concerned - it was soon apparent that
different substances were involved in the stimulation of the two
different kinds of nerves. This task would appear hopeless
considering the incredibly small quantities in which the
substances are released. Chemical methods alone were of no avail.
But Loewi carried out instead a model analysis, using those
activities which were obtained in the living organism under
changing conditions. With the sympathicus substance he was able
to prove in this way that, in a series of important points such
as destruction through oxidation and under the effects of certain
kinds of irradiation, as well as in regard to its action, it
corresponded absolutely with adrenaline. As regards the
parasympathetic substance, the task was more difficult on account
of its rapid breaking down in the presence of blood and tissue -
this supports the contention made previously that the
parasympathetic nerves act locally whereas the action of the
sympathetic nerves is more widespread. Loewi and Navratil
discovered that the breaking down could be prevented by the
addition of the vegetable base physostigmine and this made it
possible to work out a method which later made the detection of
the substance very much easier. After considerable work, Loewi
was able to determine the nature of this substance too, and to
prove that the parasympathetic substance was identical with
acetylcholine.

Loewi's discoveries have successfully withstood the searching
test of reexamination. Numerous investigations have shown also
that the release of the two substances mentioned is in no way
restricted to the nervous system of the heart. Many scientists,
notably Cannon, after comprehensive tests, have discovered that
adrenaline, or a very similar substance, appears after
stimulation of other sympathetic channels. And Engelhart, a
colleague of Loewi's, proved the existence of acetylcholine in
the anterior chamber of the eye as a result of contraction of the
pupil with the entry of light. Corresponding observations were
made for many other organs, among others by Dale and his
collaborators. Further support for the view that acetylcholine
plays a part in the body under physiological conditions was
obtained when Dale and Dudley were able to prepare from the body
small quantities of this substance.

In recent years Dale and his distinguished collaborators have
been able to add to our knowledge of the chemical transmission of
stimuli in two extremely important points. In his earlier
investigations with acetylcholine Dale was able to observe an
effect on the nerve ganglia themselves or on the ganglia of the
autonomic nervous system in which a kind of change-over takes
place. He was then led to ask whether there could be a conduction
of impulses from one nerve cell to another through the agency of
acetylcholine. Using an elegant method described by the Russian
Kibjakov, Feldberg and Gaddum were able to prove with Dale that
acetylcholine appears in the nerve ganglia after stimulation of
the connecting nerves. One can appreciate how sensitive the
methods used must be when it is realized that only one hundred
thousandth (1/100,000) of a milligram of acetylcholine a minute
was produced under favourable conditions. The role of
acetylcholine as a transmittor is not, however, restricted to the
autonomic nervous system. Dale and his pupils proved with great
skill that it plays a role in the production of muscular
contractions on the part of the motor nerves. On the one hand,
the appearance of the substance in connection with the
transmission of impulses was confirmed, on the other hand it was
also proved that under suitable experimental conditions
infinitely small quantities of acetylcholine produced muscle
contractions of a corresponding nature.

In understanding the effects of a series of different substances
on the organism, the discovery of the chemical transmission of
nerve stimuli represents a revolution. A simple and natural
explanation is found for the strange conformity between the
effect of adrenaline and acetylcholine on the one hand and the
stimulation of the sympathetic and parasympathetic systems on the
other hand; and the same applies for different substances having
a more or less similar effect. But one now has a different point
of view with regard to the effect of other substances as well,
for example the vegetable bases atropine and physostigmine.
Certainly, the observations made have a fundamental significance
for our interpretation of the physiological processes of the
nervous system, where, in the light of chemical transmission,
various so-called summation and inhibitory phenomena can be
better understood. Certain observations made during recent years
point to practical consequences which will be of value in
combating a number of pathological conditions. The importance of
any discovery, however, does not only lie in the fact that it
brings clarity and understanding to a number of observations not
previously understood; it also poses quite new problems and leads
research into new channels. The intensive work which is at
present being carried out in different laboratories on questions
connected with these observations proves convincingly what a
stimulating effect the fresh ideas connected with the
transmission of nerve stimuli have already had.

Sir Henry Dale, Professor Otto Loewi. The
Royal Caroline Institute has decided to award to both of you
jointly, this year's Nobel Prize for Physiology or Medicine for
your discoveries in respect of the chemical transmission of nerve
action. You, Professor Loewi, first succeeded in establishing
proof of such transmission and in determining the nature of the
effective substances. This work was, in part, built up on earlier
research to which you, Sir Henry, made an essential contribution.
The results were consolidated and complemented in many important
respects by you and your collaborators. You and your school have
also greatly extended the range of the new conception by later
discoveries. Through these various discoveries, which have
stimulated research in innumerable parts of the world, therefore
demonstrating once again the international character of science,
pharmacology has been very considerably influenced, and
physiology or medicine enriched to a high degree.

On behalf of the Staff of Professors, I express to you our
heartiest congratulations and hope that it may be granted to you
to take part in further research into this new territory for a
long time to come. With this hope, I have the honour to ask you
to receive the Nobel Prize for Physiology or Medicine from the
hands of His Majesty the King.